Azaindoles: Noncovalent DprE1 Inhibitors from Scaffold Morphing Efforts, Kill Mycobacterium tuberculosis and Are Efficacious <i>in Vivo</i>

Shirude, Pravin S.; Shandil, Radha; Sadler, C; Naik, Maruti; Hosagrahara, Vinayak; Hameed, Shahul; Shinde, Vikas; Bathula, Chandramohan; Humnabadkar, Vaishali; Kumar, Naveen; Reddy, Jitendar; Panduga, Vijender; Sharma, Sreevalli; Ambady, Anisha; Hegde, Naina; Whiteaker, James; McLaughlin, Robert E.; Gardner, Humphrey; Madhavapeddi, Prashanti; Ramachandran, Vasanthi; Kaur, Parvinder; Narayan, Ashwini; Guptha, Supreeth; Awasthy, Disha; Narayan, Chandan; Mahadevaswamy, Jyothi; Vishwas, K. G.; Ahuja, Vijay Kamal; Srivastava, Abhishek; Prabhakar, K. R.; Srinivasan, Bharath; Kale, Ramesh R.; Ramaiah, Manjunatha; Choudhury, Nilanjana Roy; Sambandamurthy, Vasan K.; Solapure, Suresh; Iyer, Pravin S.; Narayanan, Shridhar; Chatterji, Monalisa

doi:10.1021/jm401382v

Cited by 145 publications

(156 citation statements)

References 10 publications

Supporting

Mentioning

148

Contrasting

Order By: Relevance

“…Of note, these compounds are the first non-nitro-benzothiazinones that demonstrate significant mycobacterial activity in vitro. Several noncovalent DprE1 inhibitors have been described recently (12,18,20,21,25), and these display MIC values close to those of PyrBTZ01 and PyrBTZ02 presented in this work. In particular, TCA1 (18) and the azaindoles (26) were reported to be efficacious in a mouse model of TB, although those compounds are less potent than BTZ043 or PBTZ169 in vitro (1,3).…”

Section: Discussionsupporting

confidence: 80%

The 8-Pyrrole-Benzothiazinones Are Noncovalent Inhibitors of DprE1 from Mycobacterium tuberculosis

Makarov

Neres

Hartkoorn

et al. 2015

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Section: Discussionsupporting

confidence: 80%

The 8-Pyrrole-Benzothiazinones Are Noncovalent Inhibitors of DprE1 from Mycobacterium tuberculosis

Makarov

Neres

Hartkoorn

et al. 2015

Antimicrob Agents Chemother

View full text Add to dashboard Cite

“…DprE1, along with DprE2, catalyzes the epimerization of decaprenylphosphoryl-D-ribose to decaprenylphosphoryl-D-arabinose, the sole arabinose donor for cell wall synthesis (8). A number of DprE1 inhibitors that are bactericidal in vitro and in a mouse TB infection model have been reported in the literature, building confidence in this target (9)(10)(11)(12). Benzothiazinones (e.g., BTZ043), covalent inhibitors of the DprE1 enzyme, have been instrumental in the discovery of the target (9).…”

mentioning

confidence: 97%

“…We previously reported a novel class of DprE1 inhibitors, 1,4-azaindoles (11). This series emerged from a scaffold morphing effort and has demonstrated potent antimycobacterial activity.…”

mentioning

confidence: 99%

“…The crude product was purified by silica gel column chromatography using MeOH in DCM to afford 1- Microbiology and biochemical assays. Assays to determine the cellular activities (MICs and MBCs), the potency in an intracellular THP1 cell line model, and the IC 50 s for the DprE1 assay were carried out as described previously (11). The IC 50 is the compound concentration that results in 50% inhibition of maximal enzyme activity.…”

mentioning

confidence: 99%

See 1 more Smart Citation

1,4-Azaindole, a Potential Drug Candidate for Treatment of Tuberculosis

Chatterji

Shandil

Manjunatha

et al. 2014

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

New therapeutic strategies against multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mycobacterium tuberculosis are urgently required to combat the global tuberculosis (TB) threat. Toward this end, we previously reported the identification of 1,4-azaindoles, a promising class of compounds with potent antitubercular activity through noncovalent inhibition of decaprenylphosphoryl-␤-D-ribose 2=-epimerase (DprE1). Further, this series was optimized to improve its physicochemical properties and pharmacokinetics in mice. Here, we describe the short-listing of a potential clinical candidate, compound 2, that has potent cellular activity, drug-like properties, efficacy in mouse and rat chronic TB infection models, and minimal in vitro safety risks. We also demonstrate that the compounds, including compound 2, have no antagonistic activity with other anti-TB drugs. Moreover, compound 2 shows synergy with PA824 and TMC207 in vitro, and the synergy effect is translated in vivo with TMC207. The series is predicted to have a low clearance in humans, and the predicted human dose for compound 2 is <1 g/day. Altogether, our data suggest that a 1,4-azaindole (compound 2) is a promising candidate for the development of a novel anti-TB drug.

show abstract

“…34 Subsequent SAR study led to the identi cation of compounds 74 and 75 with improved anti TB activity. These two compounds achieved 1.5 log cfu reduction in both the acute and chronic TB mouse models after four weeks treatment at 100 mg/kg oral administration.…”

Section: 4 Azaindolesmentioning

confidence: 99%

Recent Progress on the Development of Novel Antitubercular Agents from Whole-Cell Screening Hits

Yokokawa

2014

J. Synth. Org. Chem. Jpn.

View full text Add to dashboard Cite

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) continues to be a serious major global health risk. More than one third of the world s human population is infected, resulting in 1.4 2.0 million deaths per year. The rst line therapy using a multidrug regimen has existed since the 1970s, however, there has been an alarming increase in the number of patients with multi (MDR) and extensive (XDR) drug resistant TB in recent years. Hence, there is an urgent need to develop novel drugs with new mechanisms of action and new chemotypes in order to combat drug resistant TB. A target based approach to nding new anti TB agents has been widely used, however this approach has not led to the identi cation of clinical candidates. The recent trend has been to go back to whole cell screens, in which compounds are identi ed based on their anti TB activity. Consequently, various groups have reported structurally diverse active compounds against Mtb, which were originally identi ed from phenotypic screens. This review will cover recent scienti c accounts published from these groups that have described medicinal chemistry optimization studies from whole cell screening hits. In vivo pharmacokinetics and ef cacy of optimized compounds as well as their potential molecular targets will be also discussed.

show abstract

Azaindoles: Noncovalent DprE1 Inhibitors from Scaffold Morphing Efforts, Kill Mycobacterium tuberculosis and Are Efficacious in Vivo

Cited by 145 publications

References 10 publications

The 8-Pyrrole-Benzothiazinones Are Noncovalent Inhibitors of DprE1 from Mycobacterium tuberculosis

The 8-Pyrrole-Benzothiazinones Are Noncovalent Inhibitors of DprE1 from Mycobacterium tuberculosis

1,4-Azaindole, a Potential Drug Candidate for Treatment of Tuberculosis

Recent Progress on the Development of Novel Antitubercular Agents from Whole-Cell Screening Hits

Contact Info

Product

Resources

About